Studies on nonpeptide angiotensin II receptor antagonists. I. Synthesis and biological evaluation of pyrazolo[1,5-b][1,2,4]triazole derivatives with alkyl substituents.
Alkyl-substituted pyrazolo[1,5-b][1,2,4]triazole derivatives were synthesized and evaluated for activity as angiotensin II receptor antagonists. Molecules with the (methylbiphenylyl)tetrazole moiety and N-5 were the preferred compounds. Ethyl substitutions at both C-2 and C-7 resulted in the optimal compound, 2,7-diethyl-5-[[2"-(1H -tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]tria zole (5n), with a pA2 value of 8.774 in rabbit aorta. In the in vivo tests, 5n inhibited the angiotensin II-induced pressor response in rats after oral administration. This compound also produced a dose-dependent decrease in blood pressure when administered orally to conscious furosemide-treated dogs, having a longer duration of action as compared to DuP753. These data suggest that 5a may be a useful agent for the treatment of angiotensin II-dependent disease, such as hypertension.
Okazaki
T
T
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd, Ibaraki, Japan.
Suga
A
A
Watanabe
T
T
Kikuchi
K
K
Kurihara
H
H
Shibasaki
M
M
Fujimori
A
A
Inagaki
O
O
Yanagisawa
U
U
D000284:Administration, Oral; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001013:Aorta, Thoracic; D001393:Azoles / Q000138:chemical synthesis / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004232:Diuretics / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005665:Furosemide / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001393:Azoles; D001713:Biphenyl Compounds; D004232:Diuretics; D011720:Pyrazoles; D014230:Triazoles; C105489:YM358; D005665:Furosemide; D019808:Losartan